Plasma membrane calcium channels are members of a diverse superfamily of voltage gated channel proteins. Calcium channels are membrane-spanning, multi-subunit proteins that allow controlled entry of Ca2+ ions into cells from the extracellular fluid. Excitable cells throughout the animal kingdom, and at least some bacterial, fungal and plant cells, possess one or more types of calcium channel. Nearly all “excitable” cells in animals, such as neurons of the central nervous system (CNS), peripheral nerve cells and muscle cells, including those of skeletal muscles, cardiac muscles, and venous and arterial smooth muscles, have voltage dependent calcium channels.
Multiple types of calcium channels have been identified in mammalian cells from various tissues, including skeletal muscle, cardiac muscle, lung, smooth muscle and brain. A major type of this family is the L-type calcium channels, whose function is inhibited by the familiar classes of calcium channel blockers (dihydropyridines such as nifedipine, phenylalkylamines such as verapamil, and benzothiazepines such as diltiazem). Additional classes of plasma membrane calcium channels are referred to as T-type, N-type, P-type, Q-type and R-type.
The “T-type” (or “low voltage-activated”) calcium channels are so named because their openings are of briefer duration (T=transient) than the longer (L=long-lasting) openings of the L-type calcium channels. The L, N, P and Q-type channels activate at more positive potentials (high voltage activated) and display diverse kinetics and voltage-dependent properties.
T-type calcium channels have been implicated in pathologies related to various diseases and disorders, including epilepsy, essential tremor, pain, neuropathic pain, schizophrenia, Parkinson's disease, depression, anxiety, sleep disorders, sleep disturbances, insomnia, psychosis, cardiacarrhythmia, hypertension, cancer, diabetes, infertility and sexual dysfunction (J Neuroscience, 14, 5485 (1994); Drugs Future 30(6), 573-580 (2005); EMBO J, 24, 315-324 (2005); Drug Discovery Today, 11, 5/6,245-253 (2006); Neuropharmacology 53, 308-317 (2007) and J. Biol. Chem., 283(15), 10162-10173 (2008)).
On the other hand, blockers of voltage gated sodium channels as the TTX-S channels also relates to a number of therapeutic applications.
The rat NaV1.3 channel and the human NaV1.3 channel have been cloned in 1988 and 1998/2000 respectively (FEBS Lett. 228 (1), 187-194, 1988; J. Mol. Neurosci., 10 (1), 67-70, 1998; Eur. J. Neurosci. 12 (12), 4281-4289, 2000). The NaV1.3 channel was formerly known as brain type III sodium channel. NaV1.3 is present at relatively high levels in the nervous system of rat embryos but is barely detectable in adult rats. NaV1.3 is up-regulated following axotomy in the Spinal Nerve Ligation (SNL), Chronic Constriction Injury (CCI), and diabetic neuropathy models (J Neurophysiol 82, 2776-2785, 1999. J. A. Black et al; Ann Neurol 52, 786-792, 2002. M. J. Cranner et al; Pain 83, 591-600, 1999. S. Dib-Hajj et al; J Biol Chem 279, 29341-29350, 2004. S. Hong et al; Mol Brain Res 95, 153-161, 2001. C. H. Kim et al.) The up-regulation of NaV1.3 channel contributes to rapidly repriming sodium current in small dorsal root ganglion (DRG) neurons (J Neurophysiol 82, 2776-2785, 1999. J. A. Black et al.). These observations suggest that NaV1.3 may make a key contribution to neuronal hyperexcitability.
In order to validate the contribution of NaV1.3 sodium channel in the pain states, specific antisense oligonucleotides (ASO) were used in animal pain models. NaV1.3 sodium channel ASO treatment significantly attenuated pain-related behaviors after CCI operation (J. Neurosci. 24, 4832-4839, 2004, Haim, B. C. et al.). These finding suggest that NaV1.3 sodium channel antagonist is useful to treat neuropathic pain conditions.
The NaV1.7 channel appears to be the best ‘validated’ pain target. The most exciting findings with respect to NaV1.7 have come from human genetic studies. Cox et al. (Nature 444, 894-898, 2006) discovered SCN9A mutations that cause a loss of NaV1.7 function in three families from Pakistan. Their observations link loss of NaV1.7 function with a congenital inability to experience pain, adding to the evidence indicating NaV1.7 channel as an essential participant in human nociception.
By contrast, Gain-of-function mutations have also been described that lead to enhanced pain, for example, Primary Erythermalgia in one case and Paroxysmal Extreme Pain Disorder in another. These gain-of-function mutations in patients led to different types of gating changes in NaV1.7 sodium currents and, interestingly, different degrees of effectiveness of specific sodium channel blocking drugs. The implication from these findings is that a selective NaV1.7 blocker may be an effective treatment for pain in man.
A local anaesthetic lidocaine and a volatile anaesthetic halothane are known to act on both TTX-R and TTX-S sodium channels with poor selectivity and low potency (IC50 values range from 50 mM to 10 mM). These anaesthetics at high systemic concentrations could cause devastating side effects, e.g., paralysis and cardiacarrest. However, systemic administration of lidocaine at low concentrations is effective to treat chronic pain (Trends in Pharm. Sci 22, 27-31, 2001, Baker, M. D. et al.). In rats, application of a very low dose of TTX to the DRG of the injured segment of the L5 spinal nerve significantly reduces mechanical allodynic behavior (Brain Res 871, 98-103, 2000, Lyu, Y. S. et al.). This suggests that TTX-S subtypes of sodium channels play an important role in maintaining allodynic behaviors in an animal model of neuropathic pain.
The NaV1.5 channel is also a member of TTX-resistant sodium channels. The NaV1.5 channel is almost exclusively expressed in cardiac tissue and has been shown to underlie a variety of cardiacarrhythmias and conduction disorders.
In particular, the aryl substituted carboxamide derivatives of the present invention are selective for the TTX-S channels over the NaV1.5 channel, leading to improvements in the side-effect profile.
The aryl substituted carboxamide derivatives are therefore useful for the treatment of a wide range of disorders, particularly pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including post-surgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back and orofacial pain.
Other conditions that may be treated with the picolinamide derivatives of the present invention include multiple sclerosis, neurodegenerative disorders, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder and causalgia.
WO2007120729, WO2009054982, WO2009054983, and WO2009054984 disclose a series of heterocycle amide compounds which are blockers of T-type calcium channels.
The compounds of the present invention, however, differ structurally from known compounds in the above cited arts by the presence of unique spacer between carbony group and terminal aryl group. Namely, disclosed compounds of the prior arts are introducing only one carbon atom as a spacer between carbonyl group and heteroaryl, whereas the compounds of the present invention are characterized by introducing different unique spacers between carbony group and terminal aryl group.
WO 2003037274 discloses pyrazole derivatives as sodium channel blockers. Then WO2002091830 disclosed pyridinyl fused bicyclic amides as fungicides.
The novel compounds with trifluoroethoxy or methoxy on the pyridine ring or pyrazine ring; and alkyl side chain; are useful for the treatment of a condition or disorder in which voltage gated sodium channels are involved.
On the contrary, cyclopropane carboxamide besides trifluoroethoxy or methoxy on the pyridine ring or pyrazine ring is important for the treatment of a condition or disorder in which T-type calcium channels are involved. The compounds have advantage over the compounds disclosed in WO2007120729, WO2009054982, WO2009054983, and WO2009054984 in terms of metabolism.
The above cited arts, however, have never disclosed the voltage gated sodium channels. Therefore aryl substituted carboxamide derivatives of this invention provide the first knowledge of blocking not only the T-type calcium channels but also voltage gated sodium channels.
It is an objective of the invention to provide new T-type calcium channel blockers or TTX-S blockers that are good drug candidates. Preferred compounds should bind potently to the TTX-S (NaV1.3 and NaV1.7) channels whilst showing little affinity for other sodium channels, particularly the NaV1.5 channel. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favorable pharmacokinetic properties. For example, the compounds of this invention have excellent metabolic properties comparing with the compounds disclosed in WO 2007120729, WO 2009054982, WO 2009054983, and WO 2009054984. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated.